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Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study.

  • Author(s): Aggarwal, Rahul
  • Huang, Jiaoti
  • Alumkal, Joshi J
  • Zhang, Li
  • Feng, Felix Y
  • Thomas, George V
  • Weinstein, Alana S
  • Friedl, Verena
  • Zhang, Can
  • Witte, Owen N
  • Lloyd, Paul
  • Gleave, Martin
  • Evans, Christopher P
  • Youngren, Jack
  • Beer, Tomasz M
  • Rettig, Matthew
  • Wong, Christopher K
  • True, Lawrence
  • Foye, Adam
  • Playdle, Denise
  • Ryan, Charles J
  • Lara, Primo
  • Chi, Kim N
  • Uzunangelov, Vlado
  • Sokolov, Artem
  • Newton, Yulia
  • Beltran, Himisha
  • Demichelis, Francesca
  • Rubin, Mark A
  • Stuart, Joshua M
  • Small, Eric J
  • et al.
Abstract

Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation ( P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.

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